1. Field of the Invention
The present invention relates generally to the field of neurology. More specifically, the present invention relates to an assay measuring urinary myelin basic protein like material as a correlate of multiple sclerosis status.
2. Description of the Related Art
Multiple sclerosis (MS), an inflammatory, primary demyelinating disease of the central nervous system (CNS) affecting an estimated 350,000 persons in the United States (1), is typified by a chronic and unpredictable course. This variable course and the associated heterogeneity of disease renders clinical trials involving large groups and clinical management of the individual patient problematic. Based on disease course, multiple sclerosis patients are usually categorized (2, 3) as relapsing-remitting (RR), relapsing progressive, primary chronic progressive (CP) and secondary chronic progressive according to the clinical appearance and persistence of neurological deficit. The development of disease progression, whether from onset as in primary chronic progressive-multiple sclerosis or as secondary chronic progressive-multiple sclerosis subsequent to an earlier period of relapses, can be viewed as the failure of remission. The failure of remission, or progression, is the principal cause of disability and decline in the quality of life.
The natural history of multiple sclerosis has been studied extensively for clinical features or laboratory measurements which might predict, anticipate or parallel the future course of disease. Clinical characteristics which appear to predict a future progressive course include: (1) male gender; (2) later age of onset of the disease; (3) corticospinal and cerebellar involvement; (4) increased number of relapses in the first five years; and (5) shorter interval between the first and second relapse (2-4). The clinical scales for assessing progression of disability have certain limitations (5) but, in general, the functional status in a population of multiple sclerosis patients is better than usually envisioned (6), and patients, even with chronic progressive disease may go through periods of spontaneous stability (7). This imprecision in clinical patterns and natural history requires clinical markers for signaling progression (8).
Several laboratory methods, including HLA typing (9) and cerebrospinal fluid (CSF) levels of tumor necrosis factors (10) have been reported to predict or parallel subsequent disease course in multiple sclerosis. Confirmation of these reported relationships have either not been successful (11) or conflicting (reviewed in 2). Serial cranial MRI, without or with gadolinium, represents another measure of clinical disease activity in multiple sclerosis (5, 12). Cranial MRI may predict the development of multiple sclerosis after initial signs (13), serve as a presumed surrogate marker in early multiple sclerosis (14) and demonstrate increasing lesion burden with longer duration of disease (12). The cranial MRI findings which are indicative of a chronic progressive course or which mark the transition from relapsing-remitting to chronic progressive disease are uncertain (15). Newer MRI techniques, such as magnetization transfer (16), may more accurately demonstrate the changes of chronic progressive-multiple sclerosis. Whatever the technique, cranial MRI may furnish an incomplete record about the change to a chronic progressive course which often results from involvement of the spinal cord.
Myelin basic protein (MBP), a protein of 170 amino acid residues, comprises 30% of CNS myelin proteins (17). Material, designated as myelin basic protein-like material (MBPLM), i.e., reactive with antibodies to myelin basic protein, normally exists at very low levels in CSF but increases after acute CNS myelin damage (18, 19). Serial sampling of CSF is not feasible, but the level of CSF myelin basic protein-like material in an multiple sclerosis patient with recent clinical worsening is predictive of a beneficial response to a regimen of intravenous methylprednisolone and oral prednisone (20). CSF myelin basic protein-like material has a molecular weight of &gt;30,000 and appears to be bound to a carrier molecule (21). Myelin basic protein-like material in CSF is best recognized by an antibody reactive with an epitope that is represented in myelin basic protein residues 80-89 in a conformation present in the intact myelin basic protein molecule.
Urinary myelin basic protein-like material, usually found in low levels in normal individuals, is present in elevated levels in certain multiple sclerosis patients and is quite different in size and immunochemical features from the myelin basic protein-like material present in CSF (22). It has a molecular weight of &lt;1000, is not bound to any other substances and appears to be similar to myelin basic protein residues 83-89 (22, 23). The level of urinary myelin basic protein-like material, unlike the level of myelin basic protein-like material in CSF, does not reflect acute disease activity in multiple sclerosis and correlates best with the existence of chronic progressive disease (23).
IFN.beta.-1b is the first therapeutic agent which can alter the natural history of relapsing-remitting-multiple sclerosis by reducing the number and severity of relapses and the volume of white matter involvement detected by cranial MRI (24). Although disease progression was not an end point in that trial of IFN.beta.-1b, there was a nonsignificant trend toward an effect of treatment on disease progression (24).
The prior art is deficient in the lack of effective means of determining the failure of remission or the presence of a progressive phase in patients having multiple sclerosis. The present invention fulfills this longstanding need and desire in the art.